Synthetic prostaglandins with a 4-aryloxy-3-hydroxy-1-(E)-butenyl omega chain, in particular 16-[3-(trifluoromethyl)phenoxy]-17, 18, 19, 20-tetranor-PGF.sub.2a and its esters, more particularly the isopropyl ester, are potent drugs for the treatment of glaucoma and ocular hypertension. The use of 11-oxaprostaglandins with 4-aryloxy-3-hydroxyl-1-(E)-butenyl side chains for this purpose is disclosed in WO-A-97/23223. The desired activity resides in the dextrorotary 15 R isomeric form. The structure of (+)-16-[3-(trifluoromethyl)phenoxy]-17, 18, 19, 20-tetranor-PGF.sub.2a,, isopropyl ester, is shown below. ##STR2##
U.S. Pat. No. 4,321,275 discloses a synthesis of the corresponding racemic free acid fluoprostenol, for use as a luteolytic agent and stimulant of uterine smooth muscle contraction in vertinary medicine. This compound is prepared from the Corey lactone aldehyde 4.beta.-formyl-2,3,3a.beta.,6a.beta.-tetrahydro-2-oxo-5.alpha.-(4-phenylbe nzoyloxy)-cyclopenteno[b]furan, by reaction with dimethyl 2-oxo-3-[3-(trifluoromethyl)phenoxy]-oxypropylphosphonate, thus introducing C14-16 of the omega chain. The resulting enone is transformed to fluoprostenol by non-stereoselective reduction of the keto function to the corresponding alcohol, removal of the 4-phenylbenzoyl group, protection of the two hydroxy groups with tetrahydropyranyl, reduction to the lactol, Wittig olefination with the ylide prepared from (4-carboxybutyl)triphenylphosphonium bromide and removal of the tetrahydropyranyl groups. The active 15 R diastereoisomer is obtained by chromatographic separation.
EP-A-0639563 discloses the preparation of enantiomerically enriched 16-[3-(trifluoromethyl)phenoxy]-17,18,19,20-tetrano-PGF.sub.2.infin. isopropyl ester. The active 15 R diastereoisomer of the analogue, 16-(3-chlorophenoxy)-17,18,19,20-tetranor-PGF.sub.2.infin. isopropyl ester was formed stereoselectively by reduction of the keto function of the corresponding Corey lactone enone with (-)-B-chlorodiisopinocampheylborane.
The omega chain of prostaglandins may also be introduced in its entirety by means of a coupling reaction between an organocuprate reagent and an electrophilic cyclopentane core synthon. This has the advantage of being a more convergent strategy, whereby the omega chain can be introduced already containing the requisite chirality.
Danilova et al, DOKL Chem. USSR (Engl. Transl.), 1983 273, 375-377, disclose an organocuprate coupling reaction of an alkenylcuprate formed from racemic 4-(3-trifuloromethylphenoxy)-3-(1-ethoxyethoxy)-1-iodo-1E-butene and a 2-cyclopentenone, to prepare an 11-deoxy analogue of fluoprostenol.
Tolstikov et al, J. Org. Chem. USSR (Engl. Transl), 1983, 19, 1624-1631 also disclose the racemic precursors to this 1-ethoxyethoxy ether, which are 4-[(3-trifluoromethyl)phenoxy]-1-butyn-3-ol, 4-(3-trifluoromethylphenoxy)-1-iodo-1E-buten-3-ol and their corresponding trimethylsilyl ethers.
The use of an enantiomerically enriched omega chain precursor for the preparation of PGF.sub.2a, in which the key step is the coupling of an alkenylcuprate reagent to a tricycloheptanone, is disclosed by Davies et al, J. Chem. Soc., Perkin Trans 1, 1981, 1317).
WO-A-95/33845 discloses the preparation of an enantiomerically enriched propargyl alcohol of the formula ##STR3##
wherein R.sup.1 and R.sup.2 are each H or alkyl, and R.sup.3 is optionally substituted phenyl, alkyl or cycloalkyl, by enantioselective enzyme-mediated bioresolution of the corresponding racemate. In the Examples, racemic 3-hydroxy-4-phenoxy-1-butyne was treated with isopropenyl acetate and lipase PS; the (S)-alcohol was obtained in 98% ee. The (R)-alcohol was obtained in 96% ee by non-enzymatic hydrolysis of the (R)-ester formed in the bioresolution step.